Some gut-derived metabolites such as trimethylamine-N-oxide (TMAO), indoles and phenylacetylglutamine have been strongly associated with pathological outcomes including cardiovascular diseases and death. Robust studies showed that even after adjusting for several confounding factors (i.e. other cardiovascular risk factors) these metabolites can predict death from cardiovascular diseases.22–24 However, there are conflicting observations as phenylacetylglutamine has been highlighted as a biomarker of healthy aging being associated with a shift in microbiome composition toward increased uniqueness, a marker of good health in aged subjects.25 It confirmed previous data showing elevated levels of this metabolite in centernarians.26 Phenylacetylglutamine has also been associated with an increased α-diversity and abundance of ‘beneficial’ bacteria (Akkermansia, genus from Christensenellaceae) despite its potential detrimental effects on cardiovascular health.24 Regarding TMAO, a recent work highlighted that trimethylamine (TMA) is detrimental for the BBB integrity while TMAO was protective and promoted cognitive performance in mice.27 Several other preclinical studies showed that TMAO can be beneficial against atherosclerosis, nonalcoholic fatty liver disease and glucose homeostasis impairments and is required for neurodevelopment.28–31 Indole derivatives, despite their associations with cardiovascular diseases, have been shown to exert anti-inflammatory effects on liver and to be beneficial in inflammatory bowel disease or experimental autoimmune encephalomyelitis model of multiple sclerosis.32–35 The levels of these metabolites are influenced by several factors such as dietary intake of nutrients (e.g., choline, phenylalanine and tryptophan), gut microbiota composition and function, elimination including metabolization (e.g., in the liver) and renal excretion. Interestingly, studies found that TMAO levels are greatly influenced by the presence of a type-2 diabetes or a kidney disease and that elevation of this compound can be due to confounding factor or a reverse causation.36 Fish consumption, recognized for its health-promoting effect, also leads to elevated levels of circulating TMAO.37 Better understanding of the origin of metabolites and their altered levels due to dietary intake, gut microbiota production or host metabolism will help to clarify the relationship between metabolome and health on individual level. Studying the compounds’ effect, alone or in combination, at physiological dose is also important to distinguish what happens in pathological conditions (e.g., loss of renal or hepatic function) or in basal condition. Thus, future studies should gather nutritional, metabolomic, microbial and clinical data to be able to control for confounding factors.